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Abstract

Background— Patients with non–ST-elevation acute coronary syndrome complicated by congestive heart failure (CHF) have a poor prognosis. The aims of this study were to describe the use of revascularization in non–ST-elevation acute coronary syndrome and CHF and to analyze its impact on survival.

Methods and Results— In the Global Registry of Acute Coronary Events, 29 844 patients with non–ST-elevation acute coronary syndrome were enrolled at 120 hospitals in 14 countries between April 1999 and June 2007; 4953 had CHF at presentation. One fifth of the patients with CHF underwent revascularization versus 35% of those without CHF (P<0.001). Among CHF patients, revascularized patients had lower-risk baseline clinical characteristics than nonrevascularized patients and were more likely to receive evidence-based cardiac medications. Hospital rates were not affected by revascularization (adjusted hazard ratio 0.97, 95% confidence interval 0.72 to 1.33, P=0.87). Death from discharge to 6-month follow-up was lower in patients who underwent revascularization than in those who did not (odds ratio 0.51, 95% confidence interval 0.35 to 0.74, P<0.001). This difference persisted after adjustment for GRACE risk score variables, country, and propensity for revascularization (odds ratio 0.58, 95% confidence interval 0.40 to 0.85, P=0.005). When revascularization as a time-varying covariate was taken into account in an adjusted Cox regression, the rate of death was again lower in patients undergoing revascularization (hazard ratio 0.64, 95% confidence interval 0.45 to 0.93, P=0.02).

Conclusions— This observational study suggests a low use of in-hospital revascularization in non–ST-elevation acute coronary syndrome patients with CHF. The consistent reduction in postdischarge death in revascularized patients suggests that broader application of revascularization in this high-risk group may be beneficial.

Congestive heart failure (CHF) is a common complication in patients with an acute coronary syndrome (ACS).1 In a previous report from the Global Registry of Acute Coronary Events (GRACE) involving nearly 14 000 ACS patients without prior heart failure, one fifth of those with acute myocardial infarction and 10% of those with unstable angina developed heart failure during hospitalization.2 Patients with an ACS complicated by CHF have a poor prognosis3. Patients with unstable angina who present with CHF have 4-fold higher hospital death rates than those without CHF at admission.4 ACS patients who develop acute de novo heart failure during hospitalization are at even higher risk of death than those with heart failure at admission.4–6

Clinical Perspective p 1171

European and American guidelines7–9 recommend that high-risk non–ST-elevation ACS (NSTE-ACS) patients be candidates for early coronary angiography and revascularization, yet registry data from GRACE have shown that ACS patients with heart failure are less likely than those without to undergo revascularization or receive evidence-based cardiac medications.4 The goals of the present study are to describe the use of revascularization in patients with NSTE-ACS with and without CHF and to analyze the impact of early revascularization on survival in those with CHF.

Methods

Full details of the GRACE methods have been published previously.2,10 GRACE was designed to reflect an unselected population of patients with ACS, irrespective of geographic region. A total of 123 hospitals located in 14 countries in North and South America, Europe, Australia, and New Zealand have contributed data to this observational study; 120 hospitals contributed data to the present analysis.

Adult patients (≥18 years) admitted with a presumptive diagnosis of ACS at participating hospitals were potentially eligible. Eligibility criteria were a clinical history of ACS accompanied by at least 1 of the following: ECG changes consistent with ACS, serial increases in biochemical markers of cardiac necrosis (creatine kinase-MB, creatine kinase, or troponin), and documented coronary artery disease. Patients with noncardiovascular causes for the clinical presentation, such as trauma, surgery, or aortic aneurysm, were excluded. Patients were followed up at ≈6 months by telephone or clinic visits or through calls to their primary care physician. Where required, study investigators received approval from their local hospital ethics or institutional review board.

To enroll an unselected population of patients with ACS, sites were encouraged to recruit the first 10 to 20 consecutive eligible patients each month. Standardized definitions of all patient-related variables, clinical diagnoses, and hospital complications and outcomes were used.10 This report pertains to patients with confirmed NSTE-ACS (ie, non–ST-segment elevation myocardial infarction or unstable angina) but without initial ST-segment elevation or left bundle-branch block. CHF at admission was defined with the Killip classification.11 The population selection algorithm is summarized in Figure 1. Patients with other diagnoses, missing CHF status, or cardiogenic shock or who were transferred from another hospital were excluded, as well as those for whom the revascularization status, its date, or important covariates were missing. Because of the need to ensure that CHF preceded revascularization, patients who developed CHF during hospitalization (for whom the event date was not available) were excluded from the analysis.

Statistical Analysis

Continuous variables are summarized by medians (quartiles 1 through 3 [Q1–Q3]) and were analyzed by the Wilcoxon rank sum test. Dichotomous variables are reported as frequencies and percentages and were tested with Fisher’s exact test.

A propensity analysis was performed to adjust for differences in patient characteristics between groups of CHF patients who underwent revascularization and those who did not. The multiple logistic regression model predicting revascularization contained sex, age, country of enrollment, pulse rate, serum creatinine concentration, Killip class, ST-segment elevation on admission ECG, positive initial markers of myonecrosis, and medical history (myocardial infarction, CHF, percutaneous coronary intervention [PCI], peripheral arterial disease, stroke, and hyperlipidemia). The propensity score (probability of revascularization) for patients with NSTE-ACS was categorized into quintiles (Data Supplement Appendix I). Patients with extreme probabilities (<0.07 or >0.60) of revascularization were excluded from further examination because of the inability to match revascularized and nonrevascularized patients by propensity for revascularization at these extremes (869 patients).

Associations between revascularization and both hospital and 6-month postdischarge mortality rates were analyzed by means of a 6-month Kaplan-Meier curve in the unadjusted analysis and a Cox regression in the adjusted analysis. This curve and the multiple Cox regression analyses reflect that revascularization is a time-varying covariate (Data Supplement Appendix I). Logistic regression results are also presented for comparison.

The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.

Results

Between April 1999 and June 2007, 66 456 patients with suspected ACS were enrolled in the GRACE registry. After we excluded patients who had new ST elevation/left bundle-branch block on the index ECG, did not have an ACS diagnosis, were transferred to another hospital, presented with cardiogenic shock, or developed CHF or shock during hospitalization and those with missing data, 29 844 patients remained (Figure 1); 4953 (17%) of these patients presented with CHF (Killip class II or III) at admission. Compared with patients without CHF on admission, those with CHF were older and more likely to be women (Table 1). They also had higher rates of comorbidities and cardiovascular risk factors, including diabetes mellitus and hypertension, and worse hemodynamic parameters, including higher pulse rate and lower ejection fraction. The rate of hospital revascularization was lower in patients with CHF (20% versus 35%, P<0.001).

The 4953 patients with CHF at presentation were further stratified according to whether they underwent revascularization during the index hospital admission. Those with missing data (n=450) or with extreme propensities to undergo revascularization (n=869) were excluded from the analysis. Of the 3634 remaining patients, 819 (23%) underwent a revascularization procedure during the index hospitalization: n=657 (18%) had PCI, 168 (4.6%) had coronary artery bypass graft surgery, and 6 (0.1%) had both PCI and coronary artery bypass grafting.

Demographic and Baseline Characteristics

Patients presenting with NSTE-ACS and CHF who underwent revascularization were younger and were more likely to be men, to have dyslipidemia, and to have a history of PCI (Table 2). Revascularization was associated with lower risk and better hemodynamic profile (lower heart rate and higher ejection fraction) and fewer comorbidities, including history of stroke or CHF (P=0.01 and <0.001, respectively). CHF patients who underwent revascularization were more likely to receive evidence-based cardiac medications during hospitalization, including aspirin, β-blockers, ACE inhibitors, statins, and glycoprotein IIb/IIIa inhibitors, than patients who did not undergo revascularization (Table 3). They were also more likely to receive thienopyridines. Among patients who ultimately did not undergo revascularization, 21% had undergone coronary angiography. Among revascularized patients, PCI was the most frequent method of revascularization (80% versus 21% for coronary artery bypass grafting; Table 3).

The majority of NSTE-ACS patients presenting with CHF who had a cardiac catheterization had multivessel disease (1352/1501, 90%; 93% of revascularized and 86% of nonrevascularized patients). Left main coronary disease was present in 15% of the patients who had angiography.

Factors Associated With Revascularization

In the logistic regression model for the 3634 patients with NSTE-ACS and CHF, several characteristics were associated with revascularization (country; male sex; history of PCI or hyperlipidemia; no history of myocardial infarction, CHF, or transient ischemic attack; positive initial biomarkers; younger age; lower pulse; and lower creatinine concentration). After we controlled for propensity for revascularization, most of the imbalance between patients with and without revascularization was removed (supplemental Appendix I).

Mortality

Overall, patients presenting with CHF had consistently higher mortality rates than those without (irrespective of revascularization procedures) both in the hospital (8.9% versus 0.9% overall) and during the period from discharge to 6 months after hospitalization (9.6% versus 2.9% overall; Figure 2). Patients with revascularization had lower unadjusted mortality rates than their counterparts without revascularization (Figure 2; Table 4).

Figure 2. Observed unadjusted mortality rates (A) in the hospital and (B) after discharge from the hospital to 6 months, according to use of revascularization in NSTE-ACS patients presenting with or without CHF. *P=0.05; P<0.001 for all other comparisons.

Given the differences between patients with and without revascularization, a second analysis was adjusted for the propensity to receive revascularization in a logistic regression model. This analysis was consistent with the unadjusted analysis, demonstrating improved 6-month death rates with revascularization, but revascularization was no longer statistically significantly associated with lower initial in-hospital mortality rates (Table 4).

We further analyzed revascularization as a time-varying covariate (to account for the fact that revascularization may occur at different times during hospitalization and that survival up to the date of revascularization cannot be ascribed to revascularization itself). The results of this adjusted Cox model analysis showed no statistically significant impact of revascularization on hospital death but did reveal a clear reduction in postdischarge mortality rate(Table 4), with an adjusted hazard ratio of 0.64 (95% confidence interval [CI] 0.45 to 0.93, P=0.02). Figure 3 shows the cumulative mortality rates for NSTE-ACS patients with CHF (n=3634) according to use of revascularization as a time-varying covariate, from hospital admission to 6 months later. Mortality rates started to diverge in favor of the revascularization group at approximately 2 to 3 months after hospital admission. The proportional hazards assumption was met for all variables except revascularization (protective if postdischarge, seemingly no effect if in hospital) and systolic blood pressure (a higher systolic blood pressure during the first 7 days was associated with a higher risk of death than was elevated systolic blood pressure that occurred later). The association between revascularization and death was unchanged when we accounted for the different association between systolic blood pressure and death over time.

Figure 3. Cumulative death rate from admission to 6 months by revascularization as a time-varying covariate for patients presenting with NSTE-ACS and CHF (n=3634).

Subgroup Analysis and Interaction

In patients who survived to discharge, there was a consistent benefit of in-hospital revascularization at 6-month follow-up across subgroups defined according to age, history of diabetes, and history of myocardial infarction (Figure 4). The results also appeared consistent regardless of the type of revascularization (PCI, P=0.02; coronary artery bypass grafting, P=0.24). There was, however, a significant interaction between the treatment effect (revascularization) and sex (P<0.01): Men derived a significant benefit from revascularization (adjusted hazard ratio 0.37, 95% CI 0.21 to 0.64), whereas women did not (adjusted hazard ratio 1.07, 95% CI 0.64 to 1.77).

Figure 4. Adjusted risk of death after discharge from the hospital to 6 months and use of revascularization in various subsets of patients (Cox proportional hazard analysis; n=2598). MI indicates myocardial infarction.

Discussion

In this large, contemporary, observational study, we found that the rate of revascularization during the index hospitalization was very low (23%; 819/3634) in patients with NSTE-ACS complicated by CHF, but it was associated with improved survival 6 months after discharge. This benefit was consistent for all types of NSTE-ACS, with or without elevation of markers of myocardial necrosis, regardless of the method of revascularization used, and for all subgroups analyzed except for women.

Patients who underwent revascularization had better unadjusted hospital survival; however, neither the propensity-adjusted analysis nor the adjusted Cox regression model with revascularization as a time-varying covariate showed an impact of revascularization on hospital survival, which suggests that the unadjusted difference was unlikely to be related to the revascularization but rather to the lower risk profile of revascularized patients and to a failure to account for timing of revascularization after admission in the logistic regression analysis (Data Supplement Appendix I). In contrast to the lack of hospital survival benefit, revascularization was associated with a clear survival benefit at 6 months that was consistent across patient subsets, except in women. The overall picture is therefore a combination of no early benefit related to revascularization and later clear benefit in an overall high-risk population.

The present study extends our prior observations from the same registry,4 which had examined the prevalence of heart failure across the various types of ACS and described its impact on hospital and 6-month outcomes. The present analysis describes the frequency and prognostic impact of revascularization among these patients, with adjustment for the confounding by differences in baseline characteristics, indication for PCI, and analysis of revascularization as a time-varying covariate.

The present results are consistent with the meta-analysis of randomized clinical trials that compared an early invasive strategy with an initially conservative strategy among NSTE-ACS patients,12 which showed a benefit from early intervention that was greatest for patients at highest risk. Importantly, the benefit was derived primarily from postdischarge reductions in mortality rate, with no benefit on hospital death.

In addition to randomized trials, observational studies have also suggested low use and likely underuse of revascularization in NSTE-ACS patients with CHF. A report from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association guidelines) quality-improvement initiative showed that an early invasive management strategy was not used in most high-risk patients with NSTE-ACS.13 Prior CHF and CHF at presentation were strong correlates of lack of early invasive management (OR 0.48, 95% CI 0.44 to 0.5, P<0.001, and OR 0.66, 95% CI 0.60 to 0.72, P<0.001, respectively). In an analysis of propensity-matched pairs, early intervention was associated with a lower risk of hospital death.13 A recent report from the GRACE registry also demonstrated that clinicians are frequently averse to risk in case selection, performing interventions in lower-risk patients despite greater potential clinical benefit in higher-risk individuals.14

The present study extends and complements these observations by focusing on the relatively large subset of patients with CHF at presentation. This large subset (17% of all patients) can be readily identified by clinical means (using the Killip classification) and is at very high risk of hospital and postdischarge death, as has been demonstrated in the present analysis and other analyses.4,15 In fact, among NSTE-ACS patients without signs of heart failure at admission, the mortality rate was 0.9% in hospital and 2.9% from discharge to 6 months, whereas the mortality rates were 8.9% and 9.6%, respectively, for patients with CHF. Therefore, it is likely that almost all of the gains in mortality rates to be expected in the future will be derived from improved management of patients with CHF.

Among NSTE-ACS patients with CHF, a significant proportion may not be technically suitable for revascularization, and in some patients, the extent of comorbidities may be such that the balance of benefit and periprocedural risk from revascularization may not be favorable. However, because patients with cardiogenic shock and those whose condition deteriorated during hospitalization were excluded from the present study, this cannot account for the very large proportion of patients (77%) who did not undergo revascularization and the lower rates of revascularization among CHF patients than among lower-risk patients without heart failure.

The results observed here in patients with mild to moderate heart failure are consistent with the current state of knowledge regarding the benefits of revascularization in patients with cardiogenic shock complicating acute myocardial infarction. In the landmark SHOCK (SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK) randomized trial, which compared early revascularization with initial medical stabilization in patients with acute myocardial infarction complicated by cardiogenic shock, early revascularization did not significantly reduce overall rate of death at 30 days; however, after 6 months, there was a significant survival benefit16 that was maintained for up to 6 years.17 Although the SHOCK trial pertains to ST-segment elevation myocardial infarction, the results are in line with our observation that these high-risk patients are undertreated and should be managed by early revascularization in addition to best medical treatment.

Current guidelines concur in their support of the use of early revascularization for patients with ACS and CHF; in patients with ST-segment elevation myocardial infarction, emergency primary PCI is universally recommended for patients with CHF (class IB indication).18,19 Guidelines also recommend an early invasive strategy (ie, diagnostic angiography with intent to perform revascularization) in initially stabilized patients with NSTE-ACS (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events, including patients with symptoms or signs of CHF (class IA).7,8 However, the present observations in a large, contemporary, multinational cohort reflective of current practice suggest marked underuse of revascularization among patients with NSTE-ACS complicated by CHF. The negative interaction with sex, with women deriving no benefit from revascularization and even possible harm, is consistent with previous reports of a lack of benefit of revascularization in women with NSTE-ACS.20 Although these observations must be interpreted with caution in post hoc analyses of relatively small subsets, they point to the need for further study regarding the role of revascularization in women with high-risk ACS.

Mechanisms for Benefit of Revascularization

Although the use of revascularization is the most likely explanation for the survival difference observed after hospital discharge, other factors may have played a role. In particular, the use of statins and thienopyridines was higher among heart failure patients undergoing revascularization than among those who did not. This is consistent with prior observations that patients undergoing revascularization receive more secondary-prevention drugs than patients treated medically.21,22 Given the benefits of statins and antiplatelet therapy on clinical outcomes, these differences may have impacted survival. In this regard, it is striking that the survival curves diverged several months after discharge. In patients with acute myocardial infarction who undergo early PCI, the benefit of revascularization may be attributed mainly to a reduction in the size of infarction, salvage of myocardium, and attenuation of remodeling.23 The majority of patients who present with heart failure during acute myocardial infarction have multivessel disease,24 and hence, revascularization of the infarct-related artery and early intervention in the nonculprit lesions may potentially result in electrical stabilization; recovery of stunned and hibernating myocardium; attenuation of detrimental events such as apoptosis, remodeling, development of left ventricular systolic dysfunction, and clinical signs of heart failure; and prevention of future cardiovascular events.25–27

Strengths and Limitations

GRACE is the largest multinational registry to include the complete spectrum of patients with ACS. Participating clusters reflect regional practices and outcomes but do not necessarily reflect practice for specific countries. GRACE provides a representative sample of patients with ACS who are treated in a variety of hospital and healthcare systems. Nevertheless, as a nonrandomized observational study, GRACE is subject to inherent limitations and potential biases, including the collection of nonrandomized data, missing or incomplete information, and potential confounding by drug indication or other unmeasured covariates such as left ventricular ejection fraction, which are not reported here. Heart failure was categorized with the Killip classification,11 which, although somewhat subjective, is clinically more relevant than assessment of left ventricular function and has enduring value as a simple and powerful prognostic index.15

In the present large, observational data sets, the estimated association of invasive revascularization with postdischarge survival was consistent regardless of the analytical method used, even after we accounted for prognostic variables.28 The benefit of revascularization may have been overestimated because of residual confounding related to the selection of lower-risk patients for cardiac catheterization. The magnitude of bias may be even greater, because the receipt of revascularization requires survival from admission to treatment. This was corrected in part by our treatment of revascularization as a time-dependent covariate that attributed survival to revascularization only after it actually occurred. On the other hand, the exclusion of patients who developed heart failure after admission, a group at higher risk of death even than patients with heart failure at admission,4 would be expected to minimize the benefit of revascularization but was necessary to avoid ascribing the benefits of revascularization to patients who may have developed heart failure after rather than before the procedure.

Conclusions

The observations from the present large, multinational, contemporary cohort study suggest that the use of revascularization in NSTE-ACS patients with CHF is low but is associated with a significant postdischarge survival benefit. Given that most deaths occur in this ACS subset, these observations indicate that broader use of revascularization in these patients may save lives. Further studies should delineate strategies to improve treatment of women in this patient group.

Acknowledgments

We thank the physicians and nurses participating in GRACE (Data Supplement Appendix II), and Sophie Rushton-Smith, PhD, who provided editorial support and was funded by sanofi-aventis.

Sources of Funding

GRACE is supported by an unrestricted educational grant from sanofi-aventis to the Center for Outcomes Research, University of Massachusetts Medical School. Sanofi-aventis had no involvement in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The design, conduction, and interpretation of GRACE were undertaken by an independent steering committee.

Disclosures

Dr Steg received a research grant from sanofi-aventis; serves on the speakers’ bureau of Boehringer-Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Nycomed, Medtronic, sanofi-aventis, Servier, and The Medicines Company; and serves as a consultant or on the advisory board of Astellas, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Endotis, GlaxoSmithKline, Medtronic, Merck Sharp & Dohme, Nycomed, sanofi-aventis, Servier, and The Medicines Company. Dr López-Sendón has received research grants from Bristol-Myers Squibb, Novartis, sanofi-aventis, Servier, and Pfizer and honoraria from Servier, Novartis, Pfizer, and Otsuka; he serves as a consultant or on the advisory board of Servier, Medtronic, and Novartis. Dr Feldman has received research grants from sanofi-aventis, GlaxoSmithKline, and Servier and honoraria from Boehringer Ingelheim. Dr Anderson has received research grants from sanofi-aventis, Scios, and The Medicines Company and serves as a consultant/advisory board member for sanofi-aventis, GlaxoSmithKline, Scios, and The Medicines Company. The remaining authors report no conflicts.

CLINICAL PERSPECTIVE

This study addresses the role of revascularization in patients with non–ST-elevation acute coronary syndrome who present with congestive heart failure. It is based on an analysis of 29 844 non–ST-elevation acute coronary syndrome patients enrolled in the multinational GRACE registry. Patients with congestive heart failure, who constitute a large subset (17%) of all patients, undergo in-hospital revascularization less frequently than those without heart failure (20% versus 35%, P<0.001). The baseline characteristics of patients with heart failure demonstrated higher risk than those of patients without. After adjustment for differences in baseline characteristics and propensity to undergo revascularization, and after revascularization was taken into account as a time-varying covariate, it appeared that revascularization did not affect in-hospital mortality rates but was associated with a survival benefit at 6-month follow-up. This benefit was consistent in all patient subgroups except women. These data from a large multinational registry reinforce the current guidelines’ recommendation that high-risk non–ST-elevation acute coronary syndrome patients should undergo early coronary angiography with a view to revascularization, and they are consistent with prior trials of revascularization in non–ST-elevation acute coronary syndrome or in patients with cardiogenic shock complicating myocardial infarction. Given that most deaths due to non–ST-elevation acute coronary syndrome occur in this subset, these observations indicate that broader use of revascularization in this group may save lives. Although the finding of a negative interaction between revascularization and female sex must be interpreted with caution in post hoc analyses of relatively small subsets, it emphasizes the need for further study regarding the role of revascularization in women with high-risk acute coronary syndrome.

Footnotes

The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.789685/DC1.

↵*A complete list of GRACE investigators is provided in Appendix II in the Data Supplement.